Stereotactic body radiotherapy for primary non-small cell lung cancer patients with clinical T3-4N0M0 (UICC 8th edition): outcomes and patterns of failure.

The evidence for stereotactic body radiotherapy (SBRT) is meagre for patients with clinical T3-4N0M0 non-small cell lung cancer (8th Edition of the Union for International Cancer Control (UICC)). This study retrospectively investigated clinical outcomes following SBRT for such patients. Among consecutive patients treated with SBRT, patients staged as cT3-4N0M0 by all criteria were examined, most of whom were unsuitable to chemoradiotherapy due to their fragile characters. Clinical outcomes were evaluated and factors associated with outcomes were investigated. Between 2005 and 2017, 70 eligible patients (T3: 58, T4: 12; median age 81 (63-93) years) were identified. Median follow-up duration was 28.6 (1.0-142.5) months. No adjuvant chemotherapy was administered. The 3-year local recurrence rates were 15.8% and 16.7% in T3 and T4 patients, respectively, and they were significantly lower in the high-dose group (3.1% vs 28.6%, P < 0.01). Multivariate analyses showed that the dose-volumetric factor was the significant factor for local recurrence. The 3-year regional and distant metastasis rates, cancer-specific mortality, and overall survival in T3 and T4 patients were 22.7% and 25.0%, 26.5% and 33.3%, 32.2% and 41.7%, and 39.5% and 41.7%, respectively. Only age was correlated with overall survival. Radiation pneumonitis ≥grade 3 and fatal hemoptysis occurred in 3 and 1 patients, respectively. SBRT for cT3-4N0M0 lung cancer patients achieved good local control. Survival was rather good considering that patients were usually frail, staged with clinical staging, and were not given adjuvant chemotherapy, and it may be comparable to surgery. To validate these outcomes following SBRT, a prospective study is warranted.

Clarithromycin mitigates radiation pneumonitis in patients with lung cancer treated with stereotactic body radiotherapy.

BACKGROUND: Radiation pneumonitis is a critical pulmonary toxicity after irradiation of the lung. Macrolides including clarithromycin (CAM) are antibiotics. They also have immunomodulatory properties and are used to treat respiratory inflammatory diseases. Radiation pneumonitis has similar pathology to them. Adverse reactions to macrolides are few and self-limited. We thus administered CAM to patients with high-risk factors for radiation pneumonitis, and retrospectively investigated whether CAM mitigated radiation pneumonitis following stereotactic body radiotherapy (SBRT). METHODS: Among consecutive patients treated with SBRT, we retrospectively examined lung cancer patients treated with a total dose of 40-60 Gy in 5-10 fractions and followed ≥6 months. Since January 2014, CAM has been administered in patients with pretreatment predictable radiation pneumonitis high-risk factors, including idiopathic interstitial pneumonias (IIPs), and elevated Krebs von den Lungen-6 (KL-6) and/or surfactant protein D (SP-D), and in patients developing early onset radiation pneumonitis. RESULTS: Five hundred and eighty eligible patients were identified and divided into 445 patients during the non-CAM-administration era (non-CAM-era) (before December 2013) and 136 patients during the CAM-administration era (CAM-era) (after January 2014). Median follow-up durations were 38.0 and 13.9 months, respectively. The rates of radiation pneumonitis ≥ grade 2 and ≥ grade 3 were significantly lower in CAM-era (grade ≥2, 16% vs. 9.6%, P=0.047; grade ≥3, 3.8% vs. 0.73%, P=0.037). For patients with the pretreatment predictable high-risk factors, the rate of radiation pneumonitis ≥ grade 3 was significantly lower, and that of grade ≥2 had a lower tendency (grade ≥3, 7.2% vs. 0%, P=0.011; grade ≥2, 21% vs. 9.6%, P=0.061). For patients developing early onset radiation pneumonitis, the rate of radiation pneumonitis ≥ grade 3 was also significantly lower (23% vs. 0%, P<0.05). Multivariate analysis revealed that dose-volumetric factor, the pretreatment predictable high-risk factors and non-CAM-administration era were significantly associated with or trended toward radiation pneumonitis ≥ grade 2 and ≥ grade 3. CONCLUSIONS: CAM mitigated radiation pneumonitis following SBRT. The efficacy of CAM should be confirmed in prospective studies.

Stereotactic body radiotherapy for lung cancer patients with idiopathic interstitial pneumonias.

PURPOSE: To compare toxicity and survival after stereotactic body radiotherapy (SBRT) between lung cancer patients with or without idiopathic interstitial pneumonias (IIPs), and to investigate the potential value of SBRT for the patients. METHODS: Among lung cancer patients receiving SBRT between 2005 and 2016, we evaluated those treated with a total dose of 40-60Gy in five fractions with curative intent who either were staged as cT1-4N0M0 or experienced postoperative isolated local recurrence. We analyzed the incidence of radiation pneumonitis (RP) in all patients and local recurrence and overall survival (OS) in T1a-2a patients. RESULTS: A total of 508 patients were eligible, including 42 with IIPs. The median follow-up was 32.3 (6.0-120.9) months. Significantly more patients with IIPs had grade ≥3RP than did those without IIPs (12% vs. 3%, p=0.009). The 2-year local recurrence rate was low in both groups (3.4% vs. 5.6%, p=0.38). The 2-year OS rate was significantly lower in the patients with IIPs (42.2% vs. 80.9%, p<0.001), although death from lung cancer was comparable (p=0.74). CONCLUSION: SBRT achieved excellent local control with acceptable pulmonary toxicity in lung cancer patients with IIPs. SBRT can be a reasonable option for early lung cancer patients with IIPs.

Stereotactic body radiotherapy for T3 and T4N0M0 non-small cell lung cancer.

To evaluate the outcomes and feasibility of stereotactic body radiotherapy (SBRT) for cT3 and cT4N0M0 non-small cell lung cancer (NSCLC), 25 patients with localized primary NSCLC diagnosed as cT3 or cT4N0M0, given SBRT between May 2005 and July 2013, were analyzed. All patients had inoperable tumors. The major reasons for tumors being unresectable were insufficient respiratory function for curative resection, advanced age (>80 years old) or technically inoperable due to invasion into critical organs. The median patient age was 79 years (range; 60-86). The median follow-up duration was 25 months (range: 5-100 months). The 2-year overall survival rates for T3 and T4 were 57% and 69%, respectively. The 2-year local control rates for T3 and T4 were 91% and 68%, respectively. As for toxicities, Grade 0-1, Grade 2 and Grade 3 radiation pneumonitis occurred in 23, 1 and 1 patient, respectively. No other acute or symptomatic late toxicities were reported. Thirteen patients who had no local, mediastinal or intrapulmonary progression at one year after SBRT underwent pulmonary function testing. The median variation in pre-SBRT and post-SBRT forced expiratory volume in 1 s (FEV1) values was -0.1 (-0.8-0.8). This variation was not statistically significant (P = 0.56). Forced vital capacity (FVC), vital capacity (VC), %VC and %FEV1 also showed no significant differences. SBRT for cT3 and cT4N0M0 NSCLC was both effective and feasible. Considering the favorable survival and low morbidity rate, SBRT is a potential treatment option for cT3 and cT4N0M0 NSCLC.

Threshold doses for focal liver reaction after stereotactic ablative body radiation therapy for small hepatocellular carcinoma depend on liver function: evaluation on magnetic resonance imaging with Gd-EOB-DTPA.

PURPOSE: Focal liver reaction (FLR) appears on radiographic images after stereotactic ablative body radiation therapy (SABR) in patients with hepatocellular carcinoma (HCC) and chronic liver disease. We investigated the threshold dose (TD) of FLR and possible factors affecting the TD on gadoxetate acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). METHODS AND MATERIALS: In 50 patients who were treated with SABR for small HCC and followed up by MRI for >6 months, FLR, seen as a hypointense area, was evaluated on the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. The follow-up MRI with the largest extent of FLR was fused to the planning computed tomography (CT) image, and patients with good image fusion concordance were eligible. After delineating the border of the FLR manually, a dose-volume histogram was used to identify the TD for the FLR. Clinical and volumetric factors were analyzed for correlation with the TD. RESULTS: A total of 45 patients were eligible for analysis with a median image fusion concordance of 84.9% (range, 71.6-95.4%). The median duration between SABR and subsequent hepatobiliary phase MRI with the largest extent of FLR was 3 months (range, 1-6 months). The median TD for FLR was 28.0 Gy (range, 22.3-36.4 Gy). On univariate analysis, pre-treatment Child-Pugh (CP) score and platelet count were significantly correlated with the TD. On multiple linear regression analysis, CP score was the only parameter that predicted TD. Median TDs were 30.5 Gy (range, 26.2.3-36.4 Gy) and 25.2 Gy (range, 22.3-27.5 Gy) for patients with CP-A and CP-B disease, respectively. CONCLUSION: The TD was significantly correlated with baseline liver function. We propose 30 Gy for CP-A disease and 25 Gy for CP-B disease in 5 fractions as TDs for FLR after SABR for patients with HCC and chronic liver disease. Use of these TDs will help to predict potential loss of liver tissue after SABR.

Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in 185 patients.

BACKGROUND: Since 2005, we have treated hepatocellular carcinoma (HCC) with stereotactic body radiotherapy (SBRT) uniformly at two dose levels, according to baseline liver function and normal liver dose. We retrospectively examined the outcomes for these patients. MATERIAL AND METHODS: Between 2005 and 2012, 221 HCC patients were treated with SBRT. Eligibility criteria for SBRT included a single (either solitary or recurrent) HCC lesion; unfeasible, difficult or refusal to undergo other surgery or percutaneous ablative therapies; Child-Pugh Classification (CPC) A or B; tumors ≤ 5 cm; dose to the bowels < 25 Gy/5 fractions; curative intent. Patients followed up ≥ 6 months were eligible. The prescribed dose depended on liver function and liver dose: 40 Gy for CPC-A and 35 Gy for CPC-B, in 5 fractions, requiring a 5-Gy dose reduction if the proportion of the liver receiving ≥ 20 Gy exceeded 20%. Treatment outcomes and safety were analyzed. RESULTS: A total of 185 patients (n = 48 in the 35-Gy group; n = 137 in the 40-Gy group) were eligible, with a median follow-up duration of 24 months (range 3-80). The three-year local control and overall survival rates were 91% and 70%, respectively. There were no significant differences in outcomes between dose levels: the three-year local control and overall survival rates in the 35-Gy and 40-Gy groups were 91% and 89% (log-rank p = 0.99) and 66% and 72% (p = 0.54), respectively. Acute toxicities ≥ grade 3 were observed in 24 (13.0%) patients, and 19 (10.3%) patients had worsening of CPC score by two points. All but three (1.6%) patients promptly recovered to grade 1-2. Grade 5 liver failure occurred in two patients in the 35-Gy group. CONCLUSION: SBRT for HCC was safe and provided equivalent outcomes when administered either in 35 or 40 Gy/5 fractions.

Stereotactic ablative body radiotherapy for previously untreated solitary hepatocellular carcinoma.

BACKGROUND AND AIMS: Stereotactic ablative body radiotherapy (SABR) is a relatively new treatment for hepatocellular carcinoma (HCC). The outcomes of SABR for previously untreated solitary HCC unfit for ablation and surgical resection were evaluated. METHODS: Untreated solitary HCC patients treated with SABR were retrospectively studied. Between 2005 and 2012, 221 HCC patients underwent SABR. Among them, patients with untreated solitary HCC, treated with only SABR or SABR preceded by transarterial chemoembolization, were eligible. Based on baseline liver function and liver volume receiving ≥ 20 Gy, 35-40 Gy in five fractions was prescribed to the planning target volume surface. RESULTS: Sixty-three patients were eligible, with a median follow-up duration of 31.1 (range 12.0-88.1) months. No patients were lost to follow-up. Twenty patients were treated with only SABR. In 43 patients treated with SABR preceded by transarterial chemoembolization, accumulation of lipiodol in the tumor remained complete in five, a partial defect in 38 on pre-SABR computed tomography. The 1-, 2-, and 3-year local control rates were 100%, 95%, and 92%, respectively; the intrahepatic recurrence-free rates were 76%, 55%, and 36%, respectively; and the overall survival rates were 100%, 87%, and 73%, respectively. Grade 3 laboratory toxicities in the acute, subacute, and chronic phases were observed in 10, 9, and 13 patients, respectively, and ascites occurred in one patient. CONCLUSIONS: Local control and overall survival after SABR for untreated solitary HCC were excellent despite the candidates being unfit for resection and ablation. SABR is safe and might be an alternative to resection and ablation.

Tumor response on CT following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinoma with cirrhosis.

OBJECTIVE: The purpose of this study is to evaluate the CT appearances of tumor responses following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinomas (HCCs) and to assess the relationship between tumor responses and local control. MATERIALS AND METHODS: Among 277 HCC tumors treated with stereotactic ablative body radiotherapy (35 or 40 Gy per five fractions), we selected enhanced lesions on arterial phase CT performed before stereotactic ablative body radiotherapy. Radiographic findings after stereotactic ablative body radiotherapy were evaluated during a 2-year follow-up period with the modified Response Evaluation Criteria in Solid Tumors. Local control and survival rates were calculated with the Kaplan-Meier method. RESULTS: Forty-two tumors with a median size of 2.1 cm (range, 1.0-3.8 cm) were selected with a median follow-up of 23.3 months (range, 9-56 months). Local recurrence was observed in two tumors after achieving a complete response (CR). The 2-year local control rate was 97%, and the overall survival rate was 81%. CR increased from 10 (24%) to 28 (67%) to 30 (71%) tumors at 3, 6, and 12 months after stereotactic ablative body radiotherapy. Overall CR at maximum follow-up was 39 tumors (93%), yet three enhanced tumors persisted for more than 2 years. The median time to achieve CR was 5.9 months (range, 1.2-34.2 months). CONCLUSION: The CR rate in hypervascular HCCs after hypofractionated stereotactic ablative body radiotherapy increased during the 2-year follow-up period. Cautious and continuous observation until tumor regrowth is considered relevant to evaluate a true effect of this treatment. Further studies for the optimal evaluation of treatment outcome after stereotactic ablative body radiotherapy are warranted.

Evaluation for local failure by 18F-FDG PET/CT in comparison with CT findings after stereotactic body radiotherapy (SBRT) for localized non-small-cell lung cancer.

PURPOSE: Stereotactic body radiotherapy (SBRT) is the standard care for medically inoperable early non-small-cell lung cancer (NSCLC). However, it can be difficult to differentiate local recurrence from non-recurrence radiation-induced lung opacity. We retrospectively assessed (18)F-FDG PET/CT to detect local recurrence after SBRT for NSCLC. METHODS: Between 2005 and 2011, 273 NSCLCs in 257 patients were treated with SBRT. Prescribed doses were 50Gy and 40Gy per 5 fractions for peripheral and central lesions, respectively. Tri-monthly follow-up CT scans were acquired. (18)F-FDG PET/CT scans were scheduled for screening at one year after SBRT or when recurrence was highly suspected. The dual-time-point maximum standardized uptake values (SUVmaxs) and their retention indexes (RIs) were obtained. RESULTS: A total of 214 (18)F-FDG PET/CT scans were obtained for 164 localized NSCLC tumors in 154 patients. The median follow-up period was 24.9 months (range: 6.3-72.1). Among these, 21 scans of 17 tumors were diagnosed as local recurrence. The median SUVmaxs on early and late images of recurrence and their RI were 5.0 (range: 3.2-10.7), 6.3 (range: 4.2-13.4), and 0.20 (range; 0-0.41), respectively. These were significantly higher than the respective values of non-recurrence images of 1.8 (range: 0.5-4.6), 1.7 (range: 0.5-6.1), and 0.00 (range: -0.37-0.41) (all p<0.05). For SUVmaxs on early and late images, optimal thresholds were identified as 3.2 and 4.2. Using each threshold, the sensitivity and specificity were 100% and 96-98%, respectively. CT findings were classified into ground-glass opacity (N=9), scar or fibrotic change (N=96), consolidation with air-bronchogram (N=34), consolidation only (N=22), and nodule (N=17); the respective numbers of recurrence were 0, 0, 1, 3, and 17. CONCLUSION: SUVmaxs of (18)F-FDG PET/CT could detect local recurrence after SBRT for localized NSCLC. In contrast, CT scan results had a limited ability to diagnose local recurrence.